Abstract
Adenosine activates adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits isoproterenol (100 nm)-stimulated L-type Ca2+ current (β-ICa,L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 μm, respectively. We determined whether this 11-fold difference in potency of adenosine is due to the existence of a greater A1adenosine receptor reserve for the inhibition of β-ICa,Lthan for the activation of IKAdo. Atrial myocytes were pretreated with vehicle (control) or the irreversible A1adenosine receptor antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (FSCPX) (10 and 50 nm) for 30 min, and after a 60-min washout period, concentration-response curves were determined for the adenosine-induced activation of IKAdo and inhibition of β-ICa,L. Pretreatment of atrial myocytes with 10 nm FSCPX reduced the maximal activation of IKAdo by 60% (7.9 ± 0.2 to 3.2 ± 0.1 pA/pF). In contrast, a higher concentration of FSCPX (50 nm) was required to reduce the maximal inhibition of β-ICa,L by 39% (95 ± 4% to 58.7 ± 5.6%) and caused a 15-fold increase in the EC50 value of adenosine. Values of the equilibrium dissociation constant (K A) for adenosine to activate IKAdo and inhibit β-ICa,L, estimated according to the method of Furchgott, were 2.7 and 5.6 μm, respectively. These values were used to determine the relationship between adenosine receptor occupancy and response. Half-maximal and maximal activations of IKAdorequired occupancies of 40% and 98% of A1 adenosine receptors, respectively. In contrast, occupancies of only 4% and 70%, respectively, of A1 adenosine receptors were sufficient to cause half-maximal and maximal inhibitions of β-ICa,L. Consistent with this result, a partial agonist of the A1adenosine receptor SHA040 inhibited β-ICa,L by 60 ± 3.5% but activated IKAdo by only 18.1 ± 2.5%. The results indicate that the A1 adenosine receptor is coupled more efficiently to an inhibition of β-ICa,L than to an activation of IKAdo.
Footnotes
- Received April 17, 1997.
- Accepted July 2, 1997.
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Send reprint requests to: L. Belardinelli, M.D., Professor of Medicine, University of Florida, P.O. Box 100277, Gainesville, FL 32610. E-mail: ramsey.med{at}shands.ufl.edu
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This work was supported by National Institutes of Health Grant HL56785.
- The American Society for Pharmacology and Experimental Therapeutics
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